The document summarizes key topics related to plasma cell dyscrasias and multiple myeloma, including definitions, investigations, classifications, and treatment approaches. It describes the typical features of plasma cells, abnormalities like Russell bodies and Mott cells. It outlines criteria for monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, solitary plasmacytoma, extramedullary plasmacytoma, and multiple myeloma. It discusses workup, staging, cytogenetics, and management options for multiple myeloma including stem cell transplantation and novel agents.

1. Hematology-High Yield Topics For Internal Medicine Boards and Hematology Boards Target Audience : Internal Medicine Residents, Family Medicine Residents, Hematology Fellows, Medical Students, IM Board Recertification exam aspirants Archer Internal Medicine Board Review www.CcsWorkshop.com

2. Definition: Group of lymphoid neoplasms of terminally differentiated B - cells that have in common the expansion of a single clone of immunoglobulin (Ig) - secreting plasma cells and a resultant increase in serum levels of a single homogeneous (monoclonal) Ig or it’s fragments. Plasma Cell Dyscrasias

3. Plasma Cell Plasma cells : Terminally differentiated B-cells Not normally found in peripheral blood . Account for less than 3.5% of nucleated cells in the bone marrow Oval cells with low N:C ratio. Cytoplasm is basophilic blue. Nucleus (30-40% of the cell) is oval or round and typically placed eccentrically (to one side) of the cell. A clear, colorless area adjacent to the nucleus contains Golgi apparatus Russell bodies : Globules (2-3 μm) of accumulated immunoglobulins in the cytoplasm of plasma cells. Usually round. Russell bodies may be found in normal bone marrow.

4. Plasma Cell Mott cells Plasma cells crowded with Russell bodies. An obstruction blocks the release of Golgi secretions. These cells can be found in any case of chronic plasmacytosis.

5. Plasma Cell Flame Cells Large, multinucleated plasma cells seen in Multiple myeloma. The cytoplasm resembles a red flame .

6. Plasma Cell Dyscrasias Synonyms

7. Plasma Cell Dyscrasias

8. Investigations in any suspected Monoclonal Gammopathy should include to accurately classify the disorder: Complete Blood Count ( look for anemia) Comprehensive Metabolic panel Look for renal insufficiency, hypercalcemia and subtle clues like decreased anion gap Total protein and albumin level. Determine Globulin component. Too low globulin ( < 2gm%) or Elevated Globulin ( > 3.5gm%) is concerning : Determine if Polyclonal vs. Monoclonal. Evaluate further with : Quantitative Immunoglobulins : Increase in all components usually, polyclonal. Increase in single component with reciprocal decrease of uninvolved globulin usually, may suggest monoclonal . Serum Protein Electrophoresis with immunofixation if monoclonal gammopathy is suspected. 24HR-Urine protein electrophoresis with urine immunofixation ( Serum Free Light Chain assay ( κ / λ ratio) may be used in place of UPEP} Bone marrow biopsy to evaluate % plasma cells if there is monoclonal protein or abnormal UPEP or Light chain assay or if strong clinical picture of myeloma. Skeletal survey if monoclonal gammopathy has been established ( Bone scans are usually, negative in MM) Beta-2 microglobulin and Albumin for staging and prognosis in MM ( once diagnosis is made). Investigations

9. Serum Protein Electrophoresis Serum Protein Electrophoresis : Serum is placed on special paper treated with agarose gel and exposed to an electric current. This separates the serum protein components into five classifications by size and electrical charge : serum albumin, alpha-1 globulins, alpha-2 globulins, beta globulins, and gamma globulins. Immunoglobulins ( IgG, IgM, IgA) usually migrate to gamma region but may sometimes extend to beta region. SPEP should always be performed in combination with serum immunofixation in order to determine clonality

10. SPEP SPEP showing Monoclonal Gammopathy Shows a tall “narrow” band in gamma region – “M-Spike” Also, note reduction in the normal polyclonal gamma band

11. SPEP SPEP showing Polyclonal Gammopathy Shows a broad based peak in gamma region . Seen in chronic infections, inflammation, connective tissue disease, lymphoproliferative disease.

12. Immunofixation More sensitive than SPEP Immunofixation is performed when SPEP shows a sharp “peak” or a plasma cell disorder is suspected despite a normal SPEP Immunofixation always done to confirm the presence of M-Protein and to determine the type (IgM or IgG etc and the light chain restriction : k or λ ) Why do both SPEP and IF ? Why not just IF in initial diagnosis ? Unlike SPEP, immunofixation does not give an estimate of the size of the M protein (ie, its serum concentration), and thus should be done in conjunction with electrophoresis.

13. Constitute Several Disorders Examples :

14. Denotes presence of an M-protein in a patient without a plasma cell or lymphoproliferative disorder i.e; Undetermined Significance Monoclonal Gammopathy of Undetermined Significance ( MGUS)

15. Incidence of MGUS increases with age : 1% of adults in US 3% of adults over age 70 years 11% of adults over age 80 years 14% of adults over age 90 years Significance : Can progress to monoclonal Disease IgG or IgA MGUS IgM MGUS Monoclonal Gammopathy of Undetermined Significance ( MGUS)

16. MGUS - Progression

17. And it’s Variants

18. Both criteria should be met : Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia (see CRAB) Management : Does not require any intervention Close surveillanace is necessary to ensure stability of the disease ( SPEP, CBC, Creatinine and calcium every 3 to 4 month and Skeletal Survey annually to pick up asymptomatic bone lesions) Smoldering Myeloma

19. Rare variant : About 1% of Myelomas May present with Bone lesions ( most common presenting symptom bone pain) No serum or urine monoclonal protein ( diagnosis can be missed if one is not aware of this entity, NSMM). Renal failure and hypercalcemia are generally lacking Anemia may be present Bone marrow biopsy must be performed in suspected cases: Immunostaining for a monoclonal protein on bone marrow sections may establish the diagnosis, Clonal plasma cell population in marrow. Must rule out IgD and IgE myeloma Non-Secretory Myeloma

20. Solitary Plasmacytoma Localized plasma cell tumor • Absence of a plasma cell infiltrate in random marrow biopsies • No evidence of other bone lesions by radiographic examination • Absence of renal failure, hypercalcemia or anemia

21. Plasma cell tumors that arise outside the bone marrow and no features of Multiple Myeloma Most Common Primary Sites - Head and Neck region: Upper air passages and oropharynx (May involve draining lymph nodes. Less Common Sites – Lymph nodes (primary), salivary glands, spleen, liver, etc. 25% have small monoclonal spike Rare dissemination, rarer evolution to myeloma Management : If completely resected during biopsy, no further therapy If incompletely resected, radiation therapy locally Extramedullary Plasmacytoma

22. All three criteria must be met Presence of a serum or urinary monoclonal protein Presence of 10 percent or more clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: CRAB : Hyper c alcemia (calcium > 11.5gm%), R enal Insufficiency, A nemia (hgb < 10gm%) or Lytic b one lesions Multiple Myeloma

23. Multiple Myeloma Bone Lesions : Conventional radiographs (Skeletal Survey) abnormal in 80% of patients who present with multiple myeloma

24. Multiple Myeloma Anemia: Normochromic /normocytic anemia occurs in 75% patients at diagnosis Defined as less than 10gm% in MM

25. Multiple Myeloma Major Causes : Myeloma cast nephropathy Hypercalcemia Amyloidosis Radiocontrast dye in a patient with myeloma Renal Insufficiency : Serum creatinine increased in > 50% at diagnosis Creatinine >2g/dL in 20% of patients Renal failure may be presenting manifestation

26. Multiple Myeloma Managed with urgent: 1. Corticosteroids 2.Neurosurgical intervention (laminectomy or anterior decompression in pathological #) + radiation therapy to preserve neurological function 3. Radiation therapy alone ( plasmacytoma) Spinal Cord Compression : An Oncological Emergency Spinal cord compression occurs in 5 % of patients with multiple myeloma ( plasmacytoma or pathological fracture related)

27. Multiple Myeloma - Cytogenetics Deletion 17p and Abnormalities associated with chromosome 13 carry a particularly unfavorable prognosis & respond poorly to therapy

28. Multiple Myeloma Staging : International Staging System : Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months

29. Multiple Myeloma Treatment Decisions : Indications for treatment : presence of any of CRAB ( bone lesions can be diffuse osteopenia alone) Risk Stratification : FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment

30. Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise and improved survival. Chng WJ, et al. Cancer Control. 2005;12:91-104.

31. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation

32. Initial Approach to Treatment of MM *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest

33. DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational

34. NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV

35. Transplantation vs Conventional Chemotherapy 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test

36. Autologous Stem Cell Transplantation Mel 200 mg/m 2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010.

37. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT

38. Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib

39. Proposed Mechanism of Action for Multiple Myeloma Therapies Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved.

40. Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF-  Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085.

41. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF- α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Difficult to use in renal insufficiency ( dose adjust) Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950.

42. Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert]. Renal Impairment (CrCl) Lenalidomide Dosage Moderate (30 to < 60 mL/min) 10 mg QD Severe (< 30 mL/min, not requiring dialysis) 15 mg Q 48 hrs ESRD (< 30 mL/min, requiring dialysis) 5 mg QD On dialysis days, administer following dialysis

43. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2  3  4 b5  6  7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. B O O OH N N OH Interferes with intracellular pathway that degrades proteins regulating cell cycle, apoptosis,angiogenesis H N N H

44. Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials 80% of patients entered these trials with preexisting peripheral neuropathy 3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy Richardson PG, et al. ASH 2003. Abstract 512.

45. Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest

46. Frontline Therapy in Elderly MM Patients For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment ORR: 60% Long-term CR: < 5% Trials with MP-based combinations reported improved response rates and time to progression MPT VMP NCCN Practice Guidelines. Myeloma. V.3.2010.

47. Conclusions In elderly patients, the addition of novel agents to standard MP has provided improved response rates MP alone (ORR: 50%; CR: 5%) MPR (50% to 95% reduction in myeloma protein in 55.6%) VMP (ORR: 86%) Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PE Care should be taken with bortezomib-based regimens to include herpes zoster prophylaxis

48. MM & Skeletal Complications ~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey Vertebrae: 65% Ribs: 45% Skull: 40% Shoulders: 40% Pelvis: 30% Long bones: 25% Dimopoulos M, et al. Leukemia. 2009:1-12.

49. The Central Role of the Osteoclast in Osteolytic Bone Destruction Growth factors Osteoclast differentiation Osteolysis Direct effects on osteoclast differentiation Tumor cells Bone loss Active osteoclast Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.

50. Mechanism of Bisphosphonate Inhibition of Osteoclast Activity Bisphosphonates inhibit osteoclast activity, and promote osteoclast apoptosis [1] Bisphosphonates are released locally during bone resorption [1] Bisphosphonates are concentrated under osteoclasts [1] Bisphosphonates may modulate signaling from osteoblasts to osteoclasts New bone X Bone Increased OPG production [2] Decreased RANKL expression [3] 1. Reszka AA, et al. Curr Rheumatol Rep. 2003;5:65-74. 2. Viereck V, et al. Biochem Biophys Res Commun. 2002;291:680-686. 3. Pan B, et al. J Bone Miner Res. 2004;19:147-154.

51. Recommended Doses and Infusion Times *Consider dose reduction . † 3.5mg (CrCl 50-60 mL/min); 3.3 mg (CrCl 40-49 mL/min); 3.0 mg (CrCl 30-39 mL/min). Kyle R, et al. J Clin Oncol. 2007;25:2464-2472. Drug Dose/Infusion Time Interval Estimated CrCl > 60 mL/min Pamidronate Zoledronic acid 90 mg over 2-3 hrs 4 mg over 15 mins 3-4 wks 3-4 wks Estimated CrCl 30 to < 60 mL/min Pamidronate Zoledronic acid 90 mg over 2-3 hrs* Reduced dosage † 3-4 wks 3-4 wks Estimated CrCl < 30 mL/min Pamidronate Zoledronic acid 90 mg over 4-6 hrs* Not recommended 3-4 wks

52. Bisphosphonates and Osteonecrosis Uncommon complication causing avascular necrosis of maxilla or mandible Suspect with tooth or jaw pain or exposed bone May be related to duration of therapy True incidence unknown Always enquire recent dental therapy or tooth related problems before starting bisphosphonates Papapetrou PD. Hormones (Athens). 2009;8:96-110.

53. POEMS (Osteosclerotic myeloma)

54. POEMS (Osteosclerotic myeloma)

55. Plasma Cell Leukemia >2 X 109/L plasma cells in blood ( seen on peripheral smear) Younger age Higher incidence of organomegaly and lymphadenopathy More extensive bone marrow infiltration Renal failure more common Less bone pain, fewer lytic lesions Poor response to therapy Peripheral smear showing Plasma cells

56. Monoclonal gammopathy - IgM type Plasmacytoid lymphoma Median age at diagnosis - 60 yrs Presentation : Hyperviscosity syndrome (15%) : visual impairment, neurologic manifestations Bleeding ( Acquired VWD) Cryoglobulinaemia Organomegaly, lymphadenopathy + (20%-40%) Autoimmune hemolysis - common Bone marrow involvement 90% Lytic bone lesions 2% Hypercalcemia 4% Management : Asymptomatic patients not treated until symptoms develop If Hyperviscocity features  urgent Plasmapheresis Symptomatic WM : Rituximab based therapy Waldenstrom’s Macroglobulinemia

57. Amyloidosis

58. Evaluate for amyloidosis in patients with a monoclonal protein in serum or urine plus : Nephrotic syndrome or renal insufficiency Congestive heart failure Peripheral neuropathy Carpal tunnel syndrome Hepatomegaly Idiopathic malabsorption Diagnostic Criteria: Tissue biopsy showing typical morphology Apple green birefringence under polarized light after Congo Red staining Typical fibrillar ultrastructure Diagnostic methods and Sensitivity Bone marrow examination 56% Abdominal fat aspiration 80% Combined BM & fat aspirate 89% Amyloidosis

59. Questions?